Hair and Hair Development
Hair is integral to our body image and can have a profound influence on our self-esteem and self-confidence. The hair of non-human mammal species is commonly referred to as “fur”. Unless specifically stated otherwise, or the context requires otherwise, the term “hair” as used herein shall be taken to include “fur”. The term “hair” shall also be taken to include hair on any part of a mammalian body, including the eyebrow, edge of the eyelid, armpit, and inside of the nostril, unless the context requires otherwise. Thus, hair may include head hair, eyebrow hair, eyelash, cilia, or other body hair.
Each hair comprises two structures: the shaft and the follicle. The primary component of the hair shaft is keratin. The hair shaft contains three layers of keratin, however the inner layer i.e., the medulla, may not be present. The middle layer i.e., the cortex, makes up the majority of the hair shaft. The outer layer i.e., the cuticle, is formed by tightly-packed scales in an overlapping structure. Pigment cells are distributed throughout the cortex and medulla giving the hair its characteristic color. The follicle contains several layers. At the base of the follicle is a projection called a papilla, which contains capillaries, or tiny blood vessels, that feed the cells. The living part of the hair, the area surrounding the papilla called the bulb, is the only part fed by the capillaries. The cells in the bulb divide every 23 to 72 hours, faster than any other cells in the body. The follicle is surrounded by an inner root sheath and an outer root sheath. These two sheaths protect and mould the growing hair shaft. The inner root sheath follows the hair shaft and ends below the opening of a sebaceous (oil) gland, which produces sebum, and sometimes an apocrine (scent) gland. The outer root sheath continues all the way up to the sebaceous gland. An erector pili muscle attaches below the sebaceous gland to a fibrous layer around the outer sheath. When this muscle contracts; it causes the hair to stand up.
Human skin comprises two types of hair: vellus hair and terminal hair. Vellus hair is short, fine, “peach fuzz” body hair. It is a very soft, generally pale, and short hair that grows in most places on the human body in both sexes. Venus hair is generally less than two centimeters in length, and the follicles from which vellus hair grows are not connected to sebaceous glands. It is observed most easily in those having less terminal hair to obscure it, such as women and children. It also is found in pre-adolescents and in males exhibiting male-pattern baldness. Terminal or “androgenic” hair is developed hair, which is generally longer, coarser, thicker and darker than vellus hair. Phases of growth in terminal hair are also more apparent than in vellus hair, by virtue of a generally-longer anagen phase. Terminal hair has associated sebaceous glands. In puberty, some vellus hair may develop into terminal hair. Under other conditions, such as male pattern baldness, terminal hair may revert to a vellus-like state
There are three sequential stages of hair growth: catagen, telogen, and anagen. Anagen is the active growth phase of the hair during which the cells in the root of the hair are dividing rapidly. Anagen hairs are anchored deeply into the subcutaneous fat and cannot be pulled out easily. When a new hair is formed, it pushes the club hair up the follicle, and eventually out. During this phase, the hair grows about 1 cm every 28 days. Scalp hair stays in this active phase of growth for 2-6 years. Human subjects that have difficulty growing their hair beyond a certain length may have a shortened anagen phase, whereas those having an ability to grow longer hair quickly may have a longer anagen phase. In humans, the hair on the arms, legs, eyelashes, and eyebrows generally has a short anagen compared to head or scalp hair. The catagen phase is a transitional stage that lasts for about 2-3 weeks in humans, during which time growth stops, thereby forming “club” hair. Telogen is a resting phase, lasting for about 100 days for scalp hair and much longer for other body hair. During telogen, the hair follicle is at rest, the club hair is formed, and compared to hair in anagen, the hair in telogen is located higher in the skin and can be pulled out readily. The root of telogen hair comprises a visible solid, hard, dry, and white material. Shedding of telogen hair is normal, and up to 75 hairs in telogen are shed from the human scalp daily. The shed hairs are normally replaced as about the same number of follicles enter anagen daily. At any time in normal scalp, approximately 80% to 90% of follicles are in anagen, about 1% to 3% are in catagen i.e., undergoing involution, and about 5% to 10% are in telogen.
Conditions of Hair Loss and/or Reduced Hair Growth
Hair loss or hair thinning includes any condition that results in a reduced ability to replace shed hairs or that results in enhanced shedding without their concomitant or subsequent replacement e.g., brittle hair growth, thin hair growth, short hair growth, sparse hair growth, alopecia, or hair de-pigmentation. For example, the hair cycle can become uncontrolled leading to accelerated hair loss, which may be temporary or permanent. As used herein, the term “alopecia” is used to refer to hair loss, unless specifically stated otherwise or the context requires otherwise.
Alopecia can have various causes. Hereditary androgenic alopecia is the commonest form of alopecia: it is manifested by a decrease in hair volume, or even baldness, and affects up to about 70% of men. Acute alopecia may be associated with treatment by chemotherapy, stress, severe malnutrition, iron deficiency, hormonal disorders, AIDS, or acute irradiation. Alopecia areata, which seems to be of auto-immune origin (mechanism of cellular mediation), is characterized by “patches” of varying size in one or more body places. Alopecia totalis refers to a form of alopecia areata that extends over the entire scalp, and alopecia universalis refers to a form of alopecia areata that extending over the whole body. Mechanistically, in all forms of alopecia, hair loss is directly-related to a reduced ability, slowing or failure of the follicle to enter the anagen phase, or a failure to maintain the follicle in the anagen phase, such that formation of a hair shaft reduces, is slowed or ceases altogether. Hair may move into the catagen phase before sufficient growth is achieved in the anagen phase, thus becoming in a sustained manner short and thin (i.e. “hair thinning”). Chemotherapeutic agents, radiotherapeutic agents, and other medicinal products may induce necrosis or apoptosis of the follicle as a side-effect of the therapy, also preventing the follicle to enter anagen. For example, alkylating agents e.g., temozolomide, busulfan, ifosamide, melphalan hydrochloride, carmustine, lomustine or cyclophosphamide, and antimetabolites e.g., 5-fluorouracil, capecitabine, gemcitabine, floxuridine, decitabine, mercaptopurine, pemetrexed disodium, methotrexate or dacarbazine, and natural products e.g., vincristine, vinblastine, vinorelbine tartrate, paclitaxel, docetaxel, ixabepilone, daunorubicin, epirubicin, doxorubicin, idarubicin, mitoxantrone, mitomycin, dactinomycin, irinotecan, topotecan, etoposide, teniposide, etoposide phosphate, or bleomycin sulfate, and biologics e.g., filgrastim, pegfilgrastim, bevacizumab, sargramostim or panitumumab, and hormones or hormone-related agents e.g., megestrol acetate, fluoxymesterone, leuprolide, octreotide acetate, tamoxifen citrate or fluxymesterone, and other therapeutic agents e.g., sorafenib, erlotinib, oxaliplatin, dexrazoxane, anagrelide, isotretinoin, bexarotene, vorinostat, adriamycin, cytoxan, taxol, leucovorin, oxaliplatin, and combinations of the foregoing agents are known to induce temporary or permanent alopecia.
Alopecia caused by any of the foregoing factors is a source of low self-esteem and anxiety for many patients. For those undergoing chemotherapy or radiation therapy for cancer, alopecia adds to discomfort from other adverse side-effects of the therapy e.g., nausea, skin rash, etc. Many alopecia sufferers, including patients receiving chemotherapy, choose to use wigs, hair pieces, scarves, hats or turbans to cover their bald or thinning regions. Those suffering from hair loss often experience embarrassment and fear being ridiculed by others because they look different. Some may take to wearing oversized eyeglasses in an attempt to hide the absence of eyelashes and/or eyebrows. In some subjects, alopecia may lead to depression.
Animal Models of Alopecia
There are several useful models of alopecia in humans, that have been acknowledged in the art for use in testing efficacy of alopecia remedies and other hair growth-promoting therapies.
For example, the stumptailed macaque possesses hereditary balding characteristics similar in many respects to that of androgenic alopecia in humans, is used to obtain a morphometric assessment of the rate of cyclic change of the hair follicle, including rates of cyclic progression (resting to regrowing phase, and regrowing to late anagen phase) and overall changes in follicular size. These primates are also reasonably good predictors of compound efficacy, and for example, have been employed to test efficacy of minoxidil on androgenic alopecia. Cessation of topical minoxidil treatment resulted in a renewal of the balding process, with folliculograms demonstrating increases in the proportion of resting follicles. This withdrawal from treatment apparently had no effect on hair regrowth during subsequent reapplications of minoxidil. Such treatment resulted in regrowth similar to that in the first treatment phase. Continuous treatment of topical minoxidil for 4 years has not resulted in systemic or local side effects in these animals. See e.g., Brigham et al., Clin. Dermatol. 6, 177-187, 1998; Sundberg et al., Exp. Mol. Pathol. 67, 118-130 (1999), the contents of which are incorporated herein by reference in their entirety).
Collectively, the findings obtained from studies on mouse models support the concept of alopecia areata as an autoimmune disease, and several rodent models with spontaneous and induced alopecia areata have been identified. For example, the Dundee Experimental Bald Rat (DEBR) was the first rodent model validated that developed spontaneous alopecia areata and is utilized to identify candidate alopecia areata susceptibility gene loci (Michie et al., Br J Dermatol., 125, 94-100, 1991, incorporated herein by reference). The most extensively-characterized and readily-accessible alopecia areata model is the C3H/HeJ mouse model (Sundberg et al., J Invest Dermatol., 102, 847-56, 1994, incorporated herein by reference). Aging C3H/HeJ mice (females at 3-5 months of age or older and males at more than 6 months of age) develop histopathological and immunohistochemical features of human alopecia areata. Alopecia develops diffusely or in circular areas on the dorsal surface of sufficiently-aged animals. Histologically, the changes in this non-scarring alopecia appear limited to anagen follicles surrounded by mononuclear cells composed primarily of cytotoxic or cytostatic (CD8+) and helper (CD4+) T cells, this is associated with follicular and hair shaft dystrophy. Pedigree tracing of affected C3H/HeJ mice suggests that this non-scarring alopecia may be an inherited and complex polygenic disease with a female predominance at younger ages. C3H/HeJ mice with alopecia areata can be used to study the efficacy of current treatments of alopecia areata, to study the effectiveness and safety profile of new treatment forms in established alopecia areata, and to assess the influence of various factors on the development of alopecia areata in order to prevent the onset of the disease.
Paus et al., Am. J. Pathol. 144, 719-734 (1994) have also described a rodent model of acute alopecia, the entire content of which is incorporated herein by reference. In this model, alopecia is induced by a single intraperitoneal injection of cyclophosphamide to C57 BL/6 mice. In depilated C57 BL/6 mice, the hair follicles are synchronized to anagen. By day 9 after depilation, all follicles are mature anagen VI follicles, and the skin is characterized by grey-to-black coloured hair shafts. Histologically, macroscopically, and functionally, depilation-induced anagen VI follicles are indistinguishable from spontaneously-developing anagen follicles. Around day 16 after depilation, follicle regression occurs without loss of hair shafts in the depilated animals, and skin colour converts from black to pink, indicating both induction of catagen and cessation of melanogenesis. The development of catagen follicles is indicated macroscopically by a change in skin color from black to light grey, and occurs in large waves appearing in the neck region first and then the flanks and tail regions. At day 20 after depilation, all follicles enter telogen again, characterized by change in skin color from grey to pink. When cyclophosphamide is administered to C57 BL/6 mice on day 9 after depilation, the animals show rapid and reproducible visible signs of acute alopecia dose-dependent, including significant loss of fur and premature termination of anagen characterized by depigmentation leading to a grey skin appearance by day 12-14. Thus, follicles of the neck region are generally in catagen 3-5 days after cyclophosphamide treatment. Hair shafts on the backs of animals are also removed easily by rubbing at days 12-14, and by day 15, as much as 60% of the dorsal surface may be exhibit alopecia. The color change and alopecia induced by cyclophosphamide reflect the induction of dystrophic forms of anagen and catagen in anagen VI follicles. In cyclophosphamide-treated animals, follicles also progress to telogen rapidly, as evidenced by pink skin, and rapid loss of fur due to damage of the hair follicle. Telogen is shortened following cyclophosphamide treatment, and normal telogen hair follicles enter the next hair cycle, so that animals develop new hair shafts on days 16-20 i.e., within about 7-10 days following treatment. These new hair shafts are often de-pigmented due to the presence of dystrophic anagen follicles that have not had time to produce new, normally-pigmented hair shafts. Later, pigmented hair shafts develop.
Therapy for Conditions of Hair Loss and/or Reduced Hair Growth
Existing therapies for alopecia include topical minoxidil and derivatives thereof e.g., U.S. Pat. Nos. 4,139,619 and 4,596,812, and European Pat. Nos. EP-0353123, EP-0356271, EP-0408442, EP-0522964, EP-0420707, EP-0459890 and EP-0519819, spironolactone, cyproterone acetate, flutamide, finasteride, progesterone or estrogen. Anti-androgen agents such as finasteride and minoxidil are known for treating androgenic alopecia. None of these treatments is broadly applicable. For example, such treatments may not prevent hair loss during treatment with a chemotherapeutic agent. On the other hand, such compounds may produce undesirable side-effects. For example, minoxidil is a potent vasodilator. Patients may also require frequent dosing with such compounds to achieve an effective outcome. For example, minoxidil provides very transient effects, because cessation of topical minoxidil treatment results generally in a renewal of the balding process, with folliculograms demonstrating increases in the proportion of resting follicles. Minoxidil is also recommended for administration twice-daily at 2% concentration. Notwithstanding that finasteride provides an advance over minoxidil in being deliverable orally, and is considered to be the best treatment available, about 35% or more of balding male recipients show poor or no response to that drug. Finasteride may also produce significant side-effects for some users, as a number of male users have reported erectile dysfunction, impotence, low libido, or gynecomestica after using that drug. In those males suffering such side-effects, the side effects may not disappear after ceasing finasteride.
Various prostaglandin analogs have also been disclosed for use in treatment of androgenic alopecia e.g., travoprost, voprostol, and these may also require frequent administration e.g., at least daily, however single dosages of travoprost have been described e.g., U.S. Pat. Publication 20100190853. Prostaglandin analogs are also known for use in treatment of alopecia associated with chemotherapy e.g., U.S. Pat. Publication 20110002286. Prostaglandin analogs may have a variety of adverse effects e.g., muscular constriction mediating inflammation, calcium movement, hormone regulation and cell growth control.
Midkine Family Proteins
Midkine (MK) is a growth/differentiation factor that was first discovered as a gene product expressed transiently in the process of differentiation induction of embryonic tumor cells (EC) with retinoic acid. MK is known to produce a broad range of adverse and beneficial biological effects. The expression of MK is increased in human cancer cells, including esophageal cancer, thyroid cancer, urinary bladder cancer, colorectal cancer, gastric cancer, pancreatic cancer, chest cancer, liver cancer, lung cancer, breast cancer, neuroblastoma, neuroblastoma, glioblastoma, uterine cancer, ovarian cancer, and Wilms' tumor, and is believed to promote the survival and migration of cancer cells and to facilitate neovascularization. MK is also known to promote the migration of inflammatory cells such as macrophages and neutrophil, leading to inflammation. MK is also known to stimulate the proliferation of cultured endometrial interstitial cells during endometriosis. Thus, MK inhibitors e.g., antibodies, aptamers or RNAi targeting MK protein or RNA, have been disclosed for use in treatment of a broad range of inflammatory diseases such as arthritis, autoimmune disease, rheumatic arthritis, osteoarthritis, multiple sclerosis, postoperative adhesion, inflammatory colitis, psoriasis, lupus, asthma, neutrophil functional abnormalities, and endometriosis.
Beneficial effects of MK are also known, wherein MK is also involved in promoting the formation of nascent intima following blood vessel damage and the onset of nephritis in an ischemic event, and in reducing postoperative adhesions in rheumatic subjects. Thus, MK protein has been disclosed for use in treatment of cerebral ischemia, cardiac ischemia, restenosis following vascular reconstruction surgery, cardiac coronary arterial vascular obstructive disease, cerebral vascular obstructive disease, renal vascular obstructive disease, peripheral vascular obstructive disease, and arteriosclerosis.
Pleiotrophin (PTN or HB-GAM) is a midkine family protein having approximately 50% identity at the amino acid sequence level to MK. Both MK and PTN comprise a high content of cysteine and basic residues. All the 10 cysteine residues are conserved in MK and PTN, and structurally, both can be divided into the N-domain and the C-domain. As a result of NMR analysis, it is known that these two molecules have very similar three-dimensional structures. Each domain consists of three β sheets, connected via a flexible linker region. K79, R81, and K102, considered to be important to the binding of to chondroitin sulfate and heparin, are conserved between the two proteins. MK and PTN also share three-dimensional structures wherein these basic residues appear in the vicinity of the protein surface. Accordingly, PTN has been disclosed previously for the same medical indications as MK.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge or background art in Australia or elsewhere.